Neuromuscular synapse remodeling by glial cells in aging mice

描述（由申请人提供）：在上个世纪，医学创新显著延长了人类寿命。然而，仍然没有办法减缓大脑衰老或治疗与衰老相关的神经病理学。在我们的神经系统中，胶质细胞的数量超过了神经元，胶质细胞-神经元的相互作用对于突触的形成和稳定性至关重要。已知结构改变和功能下降发生在正常老化和神经退行性脑（例如，阿尔茨海默氏症和帕金森氏症）。然而，到目前为止，人们对这种突触变化的动力学或胶质细胞的作用（如果有的话）知之甚少。研究衰老过程中突触/神经胶质变化的最佳方法是在活体动物中随时间推移跟踪相同的突触/神经胶质。目前，由于脑中神经元/神经胶质类型的可变性及其突触的小尺寸，在脑中不能容易地实现这种体内研究。脊椎动物神经肌肉接头（NMJ）是神经系统中最简单的突触。从历史上看，它极大地促进了我们对突触组织和可塑性的理解。拟议的研究计划将利用小鼠NMJ作为模型系统，以研究衰老过程中突触和相关胶质细胞（也称为终末许旺细胞或TSC）的结构可塑性。本研究将联合收割机结合体内成像技术、分子检测和电镜重建来阐明胶质细胞在衰老过程中突触重塑中的作用。该提案有三个具体目标。目的1研究在衰老过程中许旺细胞的髓鞘形成，并试图回答这种胶质细胞的变化是否会引起轴突进入部位的突触破坏，并影响整个NMJ的突触重塑。目的2研究衰老相关的突触丢失的分子机制，并测试层粘连蛋白-TSC相互作用的变化是否导致肌纤维和神经末梢之间的TSC侵袭，以及这是否导致衰老过程中突触的去除。最后，目的3旨在确定反应性TSC是否从重塑NMJ延伸过程并指导轴突发芽和突触连接的重组。从拟议的研究结果将提供重要的神经胶质细胞在衰老相关的突触损失的作用机制的见解，并确定神经胶质细胞作为治疗靶点，以改善与衰老相关的突触病理。公共卫生相关性本项目将有助于确定神经胶质细胞在神经肌肉接头老化过程中发生的突触变化中的作用。这些拟议的研究利用了新的方法，使研究人员能够跟踪活小鼠中神经胶质和突触的结构变化，这将提供有关这种动态过程如何影响正常衰老的关键信息。更重要的是，这些数据可用于创建靶向神经胶质的疗法，用于治疗以突触丧失为特征的神经退行性疾病，如帕金森病和阿尔茨海默病，或减缓正常衰老的更衰弱症状。

DESCRIPTION (provided by applicant): Medical innovations have significantly prolonged the human lifespan during the last century. However, there is still no way to slow brain aging or treat aging-related neuropathologies. Glia outnumber neurons in our nervous system and glia-neuron interactions are essential for synapse formation and stability. It is known that structural alteration and functional decline occur at synapses in both normal aging and neurodegenerative brains (e.g., Alzheimer s and Parkinson s diseases). However, so far there is little known about the dynamism of this synaptic change or the role, if any, glia play. The best way to study synapse/glia changes during aging is to follow the same synapse/glia over time in a living animal. At present, such in vivo studies cannot be easily achieved in the brain, because of the variability of neuron/glia types in the brain and the small size of its synapses. The vertebrate neuromuscular junction (NMJ) is the simplest synapse in the nervous system. Historically, it has contributed greatly to our understanding of synaptic organization and plasticity. The proposed research plan will exploit the mouse NMJ as a model system to examine the structural plasticity of the synapse and associated glia (also called terminal Schwann cells, or TSCs) during aging. The proposed studies combine the in vivo imaging technique with molecular examination and EM reconstruction to elucidate the role of glia in synapse remodeling during aging. The proposal has three specific aims. Aim 1 examines progressive myelination of Schwann cells in aging and attempts to answer whether such glial changes induce synapse disruption at the axon entry site and affect synapse remodeling in the whole NMJ. Aim 2 examines the molecular mechanism underlying aging-related synapse loss, and tests whether changes in laminin-TSC interactions lead to invasion of TSCs between muscle fibers and nerve terminals, and whether this leads to removal of synapses during aging. Finally, Aim 3 is designed to determine if reactive TSCs extend processes from remodeling NMJs and guide axon sprouting and reorganization of synaptic connections. Results from the proposed studies will provide important mechanistic insights into the role of glia in aging-related synapse loss, and identify glia as a therapeutic target to ameliorate synaptic pathologies associated with aging. PUBLIC HEALTH RELEVANCE This project will help to determine the role of glial cells in synaptic changes that occur during aging at the neuromuscular junction. These proposed studies utilize novel methods that allow the investigator to follow structural changes of glia and synapses in living mice, which will provide critical information about how this dynamic process affects normal aging. More importantly, the data may be used to create therapies that target glia for the treatment of neurodegenerative diseases that are characterized by synapse loss, such as Parkinson's Disease and Alzheimer's Disease, or to slow the more debilitating symptoms of normal aging.